Acute promyelocytic leukemia (APL) is a rare disease characterized by a chromosomal translocation between the retinoic acid receptor, alpha (RARA) gene and its counterpart gene (X), resulting in an aberrant fusion protein X-RARA, such as promyelocytic leukemia (PML)/RARA, promyelocytic leukemia zinc finger (PLZF)/RARA, NPM/RARA, NuMA/RARA or STAT5b/RARA. In APL patients, abnormal accumulation of undifferentiated promyelocytes is generally observed in bone marrow due to the blockage of cellular differentiation in myeloid lineage. Such differentiation arrest is in part resulted from dysregulation of key transcriptional regulators such as CEBPα involved in myeloid differentiation by those X-RARA proteins. All-trans retinoic acid (ATRA) treatment has been introduced for APL cells expressing those X-RARA fusions by promoting cellular differentiation and clinical remission of disease. Although APL cells expressing PLZF/RARA fusion are responsive to ATRA treatment for cell differentiation, PLZF/RARA-associated APL patients, distinct from other X-RARA types of APL patients, are resistant to ATRA therapy.
Ubiquitination-proteasome-dependent proteolysis is a major cellular pathway to control protein stability. Protein ubiquitination is a cascade reaction involving a group of specialized protein family called ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2 and ubiquitin ligase E3. Conversely, this biological process can be reversed by deubiquitinating enzymes (DUBs), which are proteases functioning by removing conjugated ubiquitin from substrates. The ubiquitination level of a substrate is regulated by its associated E3 ubiquitin ligase and/or DUB, correlating with the regulation of substrate protein stability. Thus, E3 ubiquitin ligases and DUBs are considered as potential targets for regulation of disease-associated protein stability.
DUBs have been shown to participate in several cellular functions, including DNA damage and repair, protein quality control and degradation, RNA transcription and processing, and signal transductions.
It remains unclear whether DUBs is involved in the regulation of PLZF/RARA protein stability.